Metabolic syndrome predicts lower functional recovery in female but not in male patients after an acute cardiac event

International Journal of Cardiology 135 (2009) 296 – 301 www.elsevier.com/locate/ijcard

Metabolic syndrome predicts lower functional recovery in female but not in male patients after an acute cardiac event Giuseppe Caminiti ⁎, Maurizio Volterrani, Giuseppe Marazzi, Rosalba Massaro, Cristiana Vitale, Lucia Gatta, Caterina Mammi, Marco Miceli, Giuseppe Rosano Centre for Clinical and Basic Research, Cardiovascular Research Unit, Department of Medical Sciences, IRCCS San Raffaele Roma - Roma, Italy Received 9 December 2007; accepted 6 March 2008 Available online 7 July 2008

Abstract Aims: To evaluate whether metabolic syndrome MS has a gender dependent effect on the recovery of functional capacity in patients (pts) with coronary heart disease (CHD) undergoing a cardiac rehabilitation program. Methods and Results: We studied 286 CHD patients, age 66.2 ± 10.6 (median ± SD); M/F 187/99. Patients were divided into two groups according to the presence (MS, 48%) or not (nMS, 52%) of MS. MS was present in 48% of patients. Functional capacity was assessed by the distance walked at six minute walking test (6MWT), and by a maximal exercise test. Compared to patients without MS, those with MS walked a lower distance at 6MWT (438 ± 110 vs 408 ± 123 m; p b 0.05), had a lower maximal exercise capacity (7.6 ± 1.8 vs 9.3 ± 1.2 MET; p b 0.05) and a lower heart rate recovery (HRR) (16 ± 9 vs 22 ± 8; p b 0.05). Male patients with or without MS had a similar degree of functional recovery (51%) while women with MS had a significantly lower recovery than nMS (20% vs 40%). In a multivariate logistic regression model, including body mass index, age, gender hypertension, ejection fraction and diabetes, MS predicted a reduced performance at 6MWT in the overall population (OR 1.4, 95% CI 1.7 to 2.4) and in women (OR 1.31; 95% CI 1.20–1.62), while it was not predictive in males. Conclusions: CAD patients with MS have lower functional recovery and HRR than nMS. However MS is an independent predictor of lower exercise capacity only in female gender. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Metabolic syndrome; Coronary artery disease; Gender; Exercise; Cardiac rehabilitation

1. Introduction Metabolic syndrome (MS) is an increasing clinical condition in the western countries and it is associated with a significant increase in cardiovascular morbidity. It has been estimated that 24% of US [1] and 15% of the European population have this syndrome [2].

⁎ Corresponding author. Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele - Roma, via della Pisana 235, 00163 Roma, Italy. Tel.: +39 06 660581; fax: +39 06 66058274. E-mail address: [email protected] (G. Caminiti). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.03.094

Although there might be slight disagreements on the definition of metabolic syndrome, there is enough consensus to include in the definition of MS the presence of at least three of the following conditions: hypertension, central obesity, low levels of HDL cholesterol, high levels of triglycerides, and high fasting blood glucose levels [3,4]. Because these same factors are related to the development and progression of cardiovascular diseases, there is a strong epidemiological and pathophysiological link between coronary heart disease (CHD) and MS. Indeed, MS, among patients with cardiovascular diseases, those with metabolic syndrome have a significant worse prognosis and an higher mortality [5].

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Besides its effect upon cardiovascular risk, MS is a strong and independent predictor of poor exercise capacity and low muscular strength in the general population [6,7]. Recent studies reported a lower functional capacity in CHD patients with MS than CHD subjects without MS (nMS) [8,9]. In these studies low exercise capacity was also associated to a poor survival [9,10]. Physical training, alone or in the context of cardiac rehabilitation (CR) programs, seems to be effective in improving functional capacity and reducing cardiovascular events in obese patients and in those with MS [11]. Previous studies have shown that a rehabilitation program in women with metabolic syndrome reduces likelihood of diabetes. Patients with coronary artery disease develop a severe reduction of their physical fitness and an impaired capacity to perform daily activities early after an acute cardiac event. Cardiac rehabilitation programs improve functional recovery of patients with CHD [12] but the combined impact of gender and MS is unknown. The aim of the present study was to compare the gender difference in functional recovery according to the presence of MS in a prospective cohort of patients with coronary artery disease entering a cardiac rehabilitation program after an acute cardiac event. 2. Methods We prospectively studied 336 consecutive patients referred to our cardiac rehabilitation centre between November 2004 and May 2005. Included in the study were those with established coronary artery disease, a recent (b1 month) acute ischemic cardiac event and no contraindication to undergo an aerobic cardiac rehabilitation program. At entry baseline, anthropometric, clinical, morphological and biochemical variables were collected by the medical and non-medical staff. Body mass and stature were obtained at admission and measured using a standard physician's scale and meter and the BMI (kg/m2) was calculated. Patients were classified as normal weight (BMI 18.5–24.9 kg/m2), overweight (BMI 25–29.9 kg/m2), or obese (BMI N 30 kg/m2) following the recommendations of the MS and were diagnosed according to the NCEP Adult Treatment Panel III criteria 3 which includes the presence of at least three of the following risk factors: high blood pressure (N 130/80 mm Hg), central obesity (waist circumference N102 and N 88 in men and women respectively), high triglycerides (N150 mg/dl) low HDL cholesterol (b 40 and 50 mg/dl in men and women respectively), and high fasting plasma glucose levels (N 110 mg/dl). Subjects with normal blood pressure, fasting plasma glucose, triglycerides or HDL cholesterol at the clinical evaluation who were taking medications to treat these conditions were also classified as having the disease. Blood was drawn with patients fasting in the morning following the admission.

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2.1. Functional capacity Functional capacity was evaluated by 6MWT and exercise test. 6MWT was performed at admission and before discharge. The test was performed according to the standardized procedure [13].The test was supervised by a physical therapist. Patients were asked to walk at their own maximal pace a 100 m long hospital corridor with 10 meters signs on the floor. Every minute a standard phrase of encouragement was told. Patients were allowed to stop if signs or symptoms of significant distress occurred (dyspnoea, angina), through they were instructed to resume walking as soon as possible. Results of 6MWT were expressed both in distance walked (metres) and as percentage of predicted values in healthy subjects using the Enright's equation [14]. Functional recovery was defined as the percent increase of the distance walked at II 6MWT respect to the I 6MWT. For analysis purposes low functional recovery was defined as an increase of distance walked between I and II 6MWT inferior to the median value observed in the population. 2.2. Exercise test It was performed on a treadmill using standard Bruce protocol [15,16]. During the test patients were encouraged to continue exercising until they were limited by symptoms, even if they achieved the desired goal of 85% of the maximum predicted heart rate. A resting ECG was performed and repeated at the end of each stage during exercise and during the recovery phases. Data on heart rate and blood pressure were collected during these phases. At the end of the test exercise capacity in metabolic equivalents (MET, where 1 MET is approximately equal to oxygen consumption of 3.5 ml/kg/min) was estimated. HRR was defined as the change in heart rate from peak exercise to 1 and 2 minutes later. 2.3. Physical rehabilitation program It was performed according to the AHA guidelines [17]: Every exercise session included warm-up, cool-down and flexibility exercises and 30–60 minutes of aerobic exercise with cycling or treadmill. Patients underwent two exercise sessions every day for 6 days/week over a 3 week period. 2.4. Statistical analysis Results are expressed as median ± standard deviation (SD) or percentages where appropriate. Baseline characteristics of patients with and without MS were compared with t tests for continuous variables that were normally distributed, Wilcoxon Mann–Whitney test for continuous variables that were not normally distributed, and chi-square tests for dichotomous variables. Prediction power of MS on functional recovery was evaluated trough logistic regression

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analysis. The regression model was applied to the overall population, to the male and female genders. A value of p b 0.05 was considered significant. All analyses were performed using a commercially available statistical package (SPSS for Windows 12.0, Chicago, III). 3. Results Out of 336 patients screened 286 patients (age 66.2 ±10.6; M/F 187/99) met the inclusion criteria and entered the study. Fifty patients were not included because they had primary valvular heart disease or idiopatic cardiomiopathy. Of the 286 patients included, 193 had a previous myocardial infarction, 232 had undergone coronary artery bypass surgery; 54 percutaneous coronary intervention. Baseline clinical features of our patient population is reported in Table 1. Out of 286 patients, 231 were either obese or overweight and 137 (48%) had MS. There were no significant differences in MS prevalence between men and women. Statistical comparison among baseline continuous variables of subjects with and without MS are shown in Table 2. Patients with MS had higher BMI and lower HDL-C levels. The overall hospital stay was similar in patients with and without MS (23±5 vs 21 ± 4 days); patients with and without MS underwent a similar number of training session (17 ± 7 vs 14 ± 4). No significant differences in distance walked was found at baseline 6MWT between patients with and without MS (261.8 ± 99.2 vs 300.2 ± 110.4; p N 0.05). Exercise

Table 1 Baseline clinical features of study population at admission and differences between MS and nMS groups. Population

M/F Previous Myocardial Infarction BPAC PTCA Obese/overweight/lean Hypertension Dislipidemia Diabetes COPD Ejection Fraction b 45% Atrial fibrillation Drugs Beta-blockers Ace-inibitors Statins Anti-arrhythmia Calcium channelantagonists Steroids ⁎ p b 0.05. ⁎⁎ p b 0.001.

Overall population

MS

nMS

(286)

(137)

(149)

187/99 193 (67)

83(60)/55(40) 98 (71)

104(68)/44(32) 95 (64)

232 (83) 54 (17) 73 (25)/158 (55)/55 (20) 240 (84) 203 (71) 129 (46) 73 (26) 74 (26) 41(15)

125 (91) 12 (9) 42 (31) ⁎/78 (57)/17 (12) 128 (94) ⁎ 112 (83) ⁎ 79(58) ⁎⁎ 35(25) 36(26) 19 (14)

107 (72) 42 (28) 31 (21)/80 (54)/38 (25) 112 (76) 91 (61) 50 (34) 38 (26) 38 (25) 22 (15)

249 (87) 274 (96) 223 (78) 31 (11) 66 (23)

121 (88) 133 (97) 109 (79) 12 (15.1) 29 (21)

128 (86) 141 (95) 114 (77) 19 (13) 37 (25)

17 (6)

7 (5)

10 (6)

Table 2 Statistical comparison among baseline continuous variables of subjects with MS (MS) and without MS (nMS). Parameters

Overall population MS

Age (years) 66.2 ± 10.6 Weight (kg) 74 ± 11 Height (m) 168 ± 6 Waist circumference, cm 102 ± 20 BMI, kg/m2 26 ± 9 Leucocites, cell/mmc 8.7 ± 5 Hemoglobin (g/dl) 11 ± 6 Total cholesterol, mg/dl 148 ± 14 HDL cholesterol, mg/dl 48 ± 7 Triglycerides, mg/dl 158 ± 8 Creatinine, mg/dl 1.1 ± 0.2 FC at rest, bpm 79 ± 13 Systolic blood pressure, 127 ± 18 mm Hg Diastolic blood pressure, 84 ± 9 mm Hg Ejection fraction, % 50 ± 11 PAPS, mm Hg 32 ± 13 I 6MWT, m 303 ± 110 II 6MWT, m 412 ± 126 Time exercise, min 5.8 ± 2 METS 8.4 ± 1.1 HRR I' 8.5 ± 11.1 HRR II' 21 ± 8 Stay in hospital, days 23 ± 5 Number of training sessions 16 ± 11 Rate of work during training, 52 ± 13 Watt

nMS

67 ± 7 73 ± 12 167 ± 7 105 ± 15 27 ± 9 ⁎ 7.9 ± 4.8 12 ± 2 148 ± 12 46 ± 5 ⁎ 161 ± 13 1.1 ± 0.4 79.0 ± 4 125 ± 16

66 ± 8.6 75 ± 10 169 ± 6 106 ± 17 23 ± 8 8.9 ± 3.1 11 ± 2.6 150 ± 11 51 ± 6 155 ± 11 1.0 ± 0.2 76 ± 6 131 ± 13

85 ± 7

83 ± 7

53.8 ± 8 49 ± 10 34 ± 16 30 ± 7 301 ± 99 305 ± 110 408 ± 123 ⁎ 438 ± 110 5.6 ± 2 ⁎ 7.6 ± 2 7.6 ± 1.8 ⁎ 9.3 ± 1.2 8.0 ± 6.1 9.4 ± 7.2 16 ± 9 ⁎ 22. ± 8 23 ± 5.1 21 ± 4.3 17 ± 7 14 ± 4 44 ± 14 ⁎ 56 ± 14

Data are expressed as mean ± standard deviation. ⁎ p b 0.05.

training significantly improved exercise capacity as assessed by the difference in distance walked in the first and last 6MWT in patients with and without MS (261.8 ± 99.2 vs 438.2 ± 122.9, p b 0.05; and 300.2 ± 110.4 vs 505.0 ± 110.7, p b 0.05 respectively). However distance walked at second 6MWT was significantly lower in patients with MS compared to patients without MS (438.2 ± 122.9 vs 505.0 ±110.7; p b 0.05). Distance walked at II 6MWTwas significantly lower among both men and woman with MS (Table 3). At the end of the cardiac rehabilitation program patients with MS obtained a percent increase of distance walked at

Table 3 Performance at 6MWT and at exercise test in men and women according to the presence of MS. Variable

Men

Women

Metabolic syndrome

I 6MWT II 6MWT METS

No

Yes

344 ± 92 522 ± 74 8.1 ± 2.2

325 ± 95 491 ± 99 7.7 ± 1.9

p-value

Metabolic syndrome

p-value

No

Yes

0.23 0.03 0.12

266 ± 84 354 ± 91 68 ± 18

278 ± 98 325 ± 88 52 ± 14

0.64 0.04 0.01

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6MWT of 35% and reached the 80% of predicted value, while patients without MS had 44% improvement of their 6MWT reaching the 95% of predicted value (p b 0.05). Men of both MS and nMS groups had a similar increase of functional recovery (51%) while women with MS showed a significant lower recovery than nMS (17% vs 30%; p b 0.05) (Fig. 1). Maximal exercise capacity (METS) obtained during treadmill test was significant lower in patients with MS than in those without MS (7.6 ± 1.8 vs 9.3 ± 1.2 p b 0.05). NoMS patients showed a greater exercise capacity than those with MS (minutes) (5.1 ± 2.5 vs 7.6 ± 2.7 p b 0.05). MS patients showed a statistically significant reduction of HRR at 2nd minute compared to no-MS patients (16.0 ± 9.4 vs 22.3 ± 11.8. p b 0.05) There was not significant difference for HRR at 1st minute (8.0 ± 6.1 vs 9.4 ± 7.2 p N 0.05). CHD patients without MS reached an higher rate of work than MS patients on cycloergometer during training sessions (55.9 ± 13.8 vs 43.7 ± 14.4). Regression analysis revealed that distance walked at second 6MWT was strongly and positively related to exercise capacity obtained during treadmill (r 0.74 p b 0.001). The independent prediction power of MS on functional recovery was evaluated trough a logistic regression analysis in which we included as covariates some confounding variables such as diabetes, hypertension, age, BMI, gender and ejection fraction (Table 4). After adjusting for these covariates the presence of MS resulted significantly related to a lower functional recovery in the overall population (adjusted OR 1.90; 95% CI 1.70–2.38; p b 0.001). Repeating the regression in each gender analysis, and adjusting for the same covariates, MS maintained its significant predictor power only in the female gender (OR 1.31; 95% CI 1.20– 1.62), while there was not independent association between MS and functional recovery among males. 4. Discussion The present study shows that MS is a frequent occurrence among male and female patients with CHD undergoing a

Fig. 1. Percent of functional recovery in the overall population (teal bar), in men (blue bar) and women (gold bar) according to the presence of MS. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Table 4 Logistic regression analysis evaluating the independent predictor power of MS on functional recovery in the overall population, in men and women. Lower functional recovery

Overall population Unadjusted model Adjusted model a Males Unadjusted model Adjusted model b Females Unadjusted model Adjusted model b

Odds ratio (95% CI)

p-value

2.13 (1.42–2.50) 1.90 (1.70–2.38)

b0.001 0.021

1.40 (0.98–1.91) 1.1 (0.97–1.23)

0.036 0.354

1.83 (1. 40–2.37) 1.31 (1.20–1.62)

0.002 0.038

a Adjusted for age, gender, BMI, dyslipidemia, diabetes, hypertension, and ejection fraction. b Adjusted for age, BMI, dyslipidemia, diabetes, hypertension, and ejection fraction.

cardiac rehabilitation program and that the presence of MS is associated with a reduced functional recovery in female but not in male patients. Moreover we demonstrated a severe higher limitation of functional recovery in women but not in men. The prevalence of MS reported in this study is in line with previous observations [9,10] that reported a rate of MS ranging from 50 to 58%. Savage et al. [9] reported an higher MS prevalence among women than men referred to two CR centres. We did not find any difference regarding sex distribution of MS, probably because differences exist between European and US populations in the occurrence of obesity and metabolic syndrome. In our study MS subjects had lower exercise capacity both at 6MWT and treadmill than nMS suggesting that the presence of MS affects functional capacity in patients after an acuta cardiac event. We also found that patients with MS have a limited functional recovery than nMS after training programs. The rate of work reached during training session was also significant lower for patients with MS than without MS. This finding could be consistent with a previously demonstrated reduced muscle strength in MS subject [18]. Recent studies have shown a strong association between low physical fitness and MS in CHD patients. Spies et al. [8] found that CHD patients with MS have an impaired exercise capacity (METS) and HRR compared with CHD patients without MS. In the study of Spies MS was associated with low exercise capacity independently of diabetes, hypertension and obesity. Savage et al., evaluating a large cohort of CHD patients enrolled in a cardiac rehabilitation program, reported a lower maximal exercise capacity for patients with MS [9]. Our results also show that the distance walked at predischarge 6MWT was significantly lower for MS than nMS subjects. Since the result of the discharge 6MWT was strongly and directly related to result of the exercise test our data suggest that both maximal and submaximal functional capacity seem to be affected by the presence of MS.

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To our knowledge this is the first study evaluating submaximal functional capacity in the MS using the 6MWT. Previous studies have estimated exercise capacity using a symptom-limited exercise test, that is the most accurate measure of maximal functional capacity, and they enrolled patients in stable clinical conditions and several months after an acute cardiac event [8,9]. In this study we enrolled more frail patients and this is the reason for the use of 6MWT. Patients were admitted in our division few days after the acute cardiac event when they were not able to perform a maximal exercise test. The 6MWT is particularly indicated to evaluate exercise capacity in frail, older and limited patients [19]. in which the distance walked at 6MWT more than a maximal exercise test may reflect actual physical capacity. Physical training in the contest of a CR program is useful to improve exercise capacity of CHD patients in overall population and also in patients with MS. Lavie et al. [20] have demonstrated that physical training improves not only exercise capacity in MS patients but also improves several risk factors related to MS such as insulin resistance, systolic and diastolic blood pressure, C-reactive protein and obesity indices. Katzmazyk et al. [21] reported the effects of a 20 week supervised aerobic training program on prevalence of the MS in 621 men and women who were enrolled in the HERTAGE study. After the exercise training 30.5% of the participants with the MS at baseline were no longer classified as having the MS. Comparing the results of the two 6MWT performed before and after CR program, we observed a significant improvement in the distance walked for both MS and nMS subjects. However nMS group reached an almost complete functional recovery after CR while MS subjects seem to have less benefits from CR program. It is well documented that distance walked at 6MWT is affected by several anthropometric and clinical variables such as age, sex, weight, BMI [22]. In our sample MS subjects had higher BMI than nMS. However adjusting for BMI and other confounding variables in the multivariate logistical regression model the prediction power of MS did not change in the overall population. Repeating the regression analysis separately according to gender we demonstrated an independent predictor power of MS only in the female gender. In our study male patients with MS showed a similar improvement of functional capacity than nMS while women with MS had the poorest functional recovery. There are no data for gender differences on the relation between MS and exercise capacity [23]. The mechanisms underlying the gender-related differences found in this study may be multifactorial. Some potential explanation may involve influences of sex hormones and gender differences of muscle strength. In our population, patients with MS presented a lower HRR at 2 min but not at 1 min, compared to patients without MS. HRR both at 1st and 2nd minute after exercise is used as index of sympathovagal balance in the overall population and in subjects with cardiovascular diseases [24]. The reduction in heart rate recovery, during the first minutes following exercise appears to be caused by both recovery of parasympathetic tone

and withdrawal of sympathetic tone [25]. Several population studies have shown a relation between impaired heart rate recovery following exercise and increased cardiac mortality [26,27]. Spies et al. reported that HRR at 1 minute was strongly related to the presence of MS, although this association was after adjusting for other factors. In another study HRR at 1 minute after exercise was related to measurements of 24-hour HRV and to several components of the insulin resistance syndrome in elderly men [28]. Furthermore, an improvement on HRR with physical training has been demonstrated [29]. We have studied a population of elderly CHD patients early after an acute cardiac event; other studies in more standard situations are needed to confirm our data on gender differences. In this study there is lack of data about hormonal status and muscle strength in relation to the presence of MS. In conclusion this study confirms the previous data of a high prevalence of MS among patients included in cardiac rehabilitation programs. MS predicts a low functional recovery in these patients after an acute cardiac event. The impact of MS is prevalent on female gender. References [1] Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Survey. JAMA 2002;287:356–9. [2] Hu G, Quiao Q, Tuomilehto, For the DECODE Study Group. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in non diabetic European men and women. Arch Intern Med 2004;164:1066–76. [3] NCEP expert panel. Executive summary of the third report of the National Cholesterol Education Program, Adult Treatment Panel (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. [4] Grundi SM, Cleeuman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/ National Heart, Lung and Blood Institute Scientific Statement. Circulation 2005;18:2735–52. [5] Isamana B, Almgren P, Tuomi T. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–9. [6] Jurka R, Lamonte MJ, Church TS, et al. Associations of muscle strength and fitness with metabolic syndrome in men. Med Sci Sport Exerc 2004;35:1301–7. [7] Katzmarzyk PT, Church TS, Janssen I, Ross R, Blair SN. Metabolic syndrome, obesity, and mortality: impact of cardiorespiratory fitness. Diabetes 2005;54:1222–7. [8] Spies C, Otte C, Kanaya A, Pipkin SS, Schiller NB, Whooley MA. Association of metabolic syndrome with exercise capacity and heart rate recovery in patients with coronary artery disease in the Heart and Soul study. Am J Cardiol 2005;95:1175–9. [9] Savage P, Banzer JA, Balady G, Ades DA. Prevalence of metabolic syndrome in cardiac rehabilitation/secondary prevention programs. Am Heart J 2005;149:627–31. [10] Shubair MM, Kodis J, Mekel RS. Metabolic profile and exercise capacity outcomes: their relationship to overweight and obesity in a Canadian cardiac rehabilitation setting. J Cardiopulm Rehabil 2004;24:405–13. [11] Lavie CJ. Cardiac rehabilitation and exercise training programs in metabolic syndrome and diabetes. J Cardiopulm Rehabil 2005;25:59–66. [12] U.S. Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Washington, DC: Office of Disease Prevention and Health Promotion; 1996.

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